Computerized features of spatial interplay of tumor-infiltrating lymphocytes predict disease recurrence in p16+ oropharyngeal squamous cell carcinoma: A multisite validation study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6559-6559
Author(s):  
Germán Corredor ◽  
Cheng Lu ◽  
Can Koyuncu ◽  
Kaustav Bera ◽  
Paula Toro ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
High Risk ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Univariate Analysis ◽  
Tumor Infiltrating Lymphocytes ◽  
Disease Recurrence ◽  
Oropharyngeal Squamous Cell Carcinoma ◽  
Training Set ◽  
Infiltrating Lymphocytes

6559 Background: While overall, patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) have a favorable prognosis, subsets of patients experience disease recurrence (DR) and death despite aggressive multimodality treatment. Aside from routine staging criteria, there are no biomarkers of tumor behavior routinely employed in OPSCC to identify patients at higher risk of DR. In this study we sought to evaluate whether the interplay between tumor-infiltrating lymphocytes (TILs) & cancer cells, in both stromal and epithelial compartments from digitized H&E-stained slides, can predict DR in OPSCC patients. Methods: OPSCC resected specimens from 354 patients (66 with DR) were retrospectively collected from 3 different sites. 107 (16 DR) patients from site 1 formed the training set and 247 (50 DR) patients from sites 2 & 3 formed the independent validation cohort. Computerized algorithms automatically identified 4 types of nuclei (TILs & non-TILs in both stromal & epithelial regions), defined clusters for each nuclei type based on cell proximity, and used network graph concepts to capture measurements relating to the arrangement of these clusters. The top 10 features determined by a statistical selection method (LASSO) were used to train a Cox regression model that assigns a risk of DR to each patient on the training set. The median risk score was used as threshold for stratifying patients on the validation set into low and high-risk of DR. Survival analysis was used to evaluate the stratification given by the trained model. Results: Patients identified by the TIL interplay model as high risk for DR had statistically worse disease specific survival. Univariate analysis yielded an HR=2.49 (95% CI: 1.22-5.07, p=0.04) for site 2 and HR=3.62 (95% CI: 1.39-9.43, p=0.03) for site 3. Multivariate analysis controlling the effect of different clinical variables is shown in the attached table. Conclusions: We introduce a prognostic model based on the automated quantification of the interplay between tumor microenvironment cells that is able to help distinguish OPSCC patients with higher DR risk from those who will experience longer disease-free survival. [Table: see text]

Combination of tumor multinucleation and spatial arrangement of tumor-infiltrating lymphocytes to predict overall survival in oropharyngeal squamous cell carcinoma: A multisite study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6566-6566
Author(s):  
Can Koyuncu ◽  
Germán Corredor ◽  
Cheng Lu ◽  
Paula Toro ◽  
Kaustav Bera ◽  
...  
Keyword(s):  
Overall Survival ◽  
Squamous Cell Carcinoma ◽  
High Risk ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Univariate Analysis ◽  
Tumor Infiltrating Lymphocytes ◽  
Spatial Arrangement ◽  
Risk Scores ◽  
Infiltrating Lymphocytes

6566 Background: Oropharyngeal squamous cell carcinoma patients can have major morbidity from current treatment regimens, necessitating accurate identification of patients with aggressive versus indolent tumors. In this study, we sought to evaluate whether the combination of computer extracted features of tumor cell multinucleation (MN) and spatial interplay of tumor-infiltrating lymphocytes (TILs) is prognostic of overall survival (OS) in OPSCC patients. Methods: OPSCC specimens from 688 patients were retrospectively collected from 3 different sites. 141 patients from site 1 formed the training set (D1) and 322 patients from site 2 and 225 patients from site 3 formed the independent validation cohort (D2, n = 547). A machine learning (ML) model was employed to automatically calculate a Multi-nucleation risk index (MNI), which is the ratio of the number of MN to the number of epithelial cells, to each patient. A separate ML model was also used to capture measurements related to the interplay between TILs and tumor cells (SpaTIL), which were then used to compute a risk score using a Cox regression model. The median value of both the MNIs and the SpaTIL risk scores in D2 were used to identify patients as either low- or high-risk. A definitive label was assigned to each patient by combining the class labels obtained from the MNI and SpaTIL models using a logical AND operation. Results: In D2, the patients with high-risk scores had statistically significantly worse survival in univariate analysis. The univariate analysis yielded an HR = 1.91 (95% CI: 1.25-2.93, p = 0.0027) for D. Multivariate analysis controlling the effect of different clinical variables is shown in the table. Conclusions: We presented a computational pathology approach to prognosticate disease outcome in OPSCC by combining features relating to density of multinucleation and spatial arrangement of TILs and validated the approach on a large multi-site dataset. With additional validation the approach could potentially help identify OPSCC patients who could benefit from de-escalation of therapy. [Table: see text]

Computer extracted features of nuclear architecture in H&E sections to predict disease recurrence in oropharyngeal squamous cell carcinoma patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17536-e17536
Author(s):  
Cheng Lu ◽  
James Lewis ◽  
Anant Madabhushi
Keyword(s):  
Squamous Cell Carcinoma ◽  
High Risk ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Characteristic Curve ◽  
Strong Association ◽  
Nuclear Architecture ◽  
Disease Recurrence ◽  
Oropharyngeal Squamous Cell Carcinoma ◽  
Cell Cluster

e17536 Background: Most patients with oropharyngeal squamous cell carcinoma (OPSCC) are cured of their disease but 10-20% will develop recurrence. Identifying high risk patients is key to tailoring therapy and reducing treatment-related morbidity. In this study, we present initial findings using computerized analysis of local nuclear architecture from digitized H&E tissue sections of OPSCC via a new algorithm called cell run-length features (CRF) to distinguish patients with more versus less aggressive disease. Methods: H&E stained tissue microarray sections of 160 primary p16+ OPSCC were digitally scanned. Our CRF analysis involved 1) nuclei segmentation, 2) creation of local cell cluster graphs based on proximity of nuclei, and 3) computing CRF for each cell cluster graph. The CRF reflects the total number of different ways/runs that the graph vertices can be traversed. A higher CRF reflects more complex nuclear spatial architecture, while a lower CRF reflects the converse. A series of CRF features relating to statistics of the graph runs across the image are then extracted,. The top 5 predictive features were identified via Wilcoxon Rank Sum Test and then evaluated in conjunction with a binary quadratic classifier via 5-fold cross validation. Results: The top ranked features were related to CRF non-uniformity (i.e. reflecting the variation of complexity of different nuclei clusters) and the classifier yielded a mean area under the receiver operating characteristic curve of 0.75 in discriminating patients who did and did not have disease progression. Patients with high risk CRF values were 5.7 times more likely to suffer disease recurrence than those without. While the whole cohort had a disease recurrence rate of 12.5%, those with low CRF values developed recurrence in only 1.875%. Conclusions: CRF features demonstrate a strong association with disease recurrence in patients with p16 positive OPSCC. Our preliminary findings suggest that measurements related to local arrangement of nuclei have potential in the risk assessment of patients with p16 positive OPSCC. The findings will need to be independently validated in a separate, powered cohort of patients.

scholarly journals Prognostic and Therapeutic Implications of Immune Classification by CD8+ Tumor-Infiltrating Lymphocytes and PD-L1 Expression in Sinonasal Squamous Cell Carcinoma

2021 ◽  
Vol 22 (13) ◽  
pp. 6926
Author(s):  
Rocío García-Marín ◽  
Sara Reda ◽  
Cristina Riobello ◽  
Virginia N. Cabal ◽  
Laura Suárez-Fernández ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Survival Rate ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Survival Data ◽  
Checkpoint Inhibitors ◽  
Therapeutic Option ◽  
Univariate Analysis ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes

Sinonasal squamous cell carcinoma (SNSCC) is an aggressive tumor predominantly arising in the maxillary sinus and nasal cavities. Advances in imaging, surgical and radiotherapeutic techniques have reduced complications and morbidity; however, the prognosis generally remains poor, with an overall 5-year survival rate of 30–50%. As immunotherapy may be a new therapeutic option, we analyzed CD8+ tumor-infiltrating lymphocytes (TILs) and the tumor microenvironment immune type (TMIT, combining CD8+ TILs and PD-L1) in a series of 57 SNSCCs. Using immunohistochemistry, tissue samples of 57 SNSCCs were analyzed for expression of CD8 on TILs and of PD-L1 on tumor cells. The results were correlated to the clinical and survival data. In total, 88% (50/57) of the tumors had intratumoral CD8+ TILs; 19% (11/57)—CD8high (>10%); and 39/57 (68%)—CD8low (1–10%). PD-L1 positivity (>5%) was observed in 46% (26/57) of the SNSCCs and significantly co-occurred with CD8+ TILs (p = 0.000). Using univariate analysis, high intratumoral CD8+ TILs and TMIT I (CD8high/PD-L1pos) correlated with a worse survival rate. These results indicate that SNSCCs are immunogenic tumors, similar to head and neck squamous cell carcinomas. Nineteen percent of the cases were both CD8high and PD-L1pos and this subgroup may benefit from therapy with immune checkpoint inhibitors.

scholarly journals The role of tumor infiltrating lymphocytes (TILs) and the ratios between different subsets serve as prognostic factors in hypopharyngeal squamous cell carcinoma

2020 ◽  
Author(s):  
Jie Wang ◽  
Shu Tian ◽  
Ji Sun ◽  
Jiahao Zhang ◽  
Lan Lin ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Immune Cells ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Tumor Infiltrating Lymphocytes ◽  
Free Survival ◽  
Hypopharyngeal Squamous Cell Carcinoma ◽  
Infiltrating Lymphocytes

Abstract Background: Cancer cells induce the infiltration of various immune cells located or distributed in different sites and playing multiple roles, which have recently been proposed to predict clinical outcomes. We therefore studied the prognostic significance based on the presence of tumor infiltrating lymphocytes (TILs) and the ratios between different types of immune cells in hypopharyngeal squamous cell carcinoma (HPSCC).Methods: We retrospectively analysed 132 consecutive patients diagnosed with HPSCC in 2013-2017. Tumoral parenchyma were immunohistochemically counted manually for the number of CD8, CD4 and Foxp3. The ratios of CD8/Foxp3 and CD4/CD8 were calculated for each specimen, and analyzed with respect to patient clinicopathologic variables and prognosis. Results: HPSCC patients with high levels of TILs showed evidently correlations with well differentiated tumors (P < 0.05). Increased Foxp3+ TIL is also significantly associated with Stage and T stage (P =0.048 and P= 0.046, respectively). Kaplan-Meier analysis showed that high CD8 and FoxP3 infiltration correlated with favorable overall survival (OS, P = 0.019 and P = 0.001), disease-free survival (DFS, P = 0.045 and P = 0.028) and distant metastasis-free survival (DMFS, P = 0.034 and P = 0.009), respectively, but only FoxP3 displayed prognostic significance for DMFS in multivariate analysis (MVA). In lymphocyte ratios analysis, CD8/FoxP3 appeared to play a pivotal role, patients with high CD8/FoxP3 ratio had a superior 3-year DFS and DMFS compared with the low value of this parameter in both univariate analysis (UVA) and MVA (P = 0.015 and P=0.001). Meanwhile, high CD4/CD8 ratio had significantly better DFS and local relapse-free survival (LRFS) in UVA, and exhibited an independent prognostic factor for improved LRFS in MVA (P = 0.040).Conclusion: Although high TILs were determined to be prognostically significant in HPSCC, the ratios of these subsets may be more informative. Particularly, higher ratio of CD8/Foxp3 accurately predict prognosis for improved DFS and DMFS, and increment of CD4/CD8 ratio was an independent predictor for favorable LRFS.

scholarly journals LAG-3, TIM-3 and VISTA Expression on Tumor-Infiltrating Lymphocytes in Oropharyngeal Squamous Cell Carcinoma—Potential Biomarkers for Targeted Therapy Concepts

2020 ◽  
Vol 22 (1) ◽  
pp. 379
Author(s):  
Nora Wuerdemann ◽  
Katharina Pütz ◽  
Hans Eckel ◽  
Rishabh Jain ◽  
Claus Wittekindt ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Clinical Trials ◽  
T Cell ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Immune Checkpoint ◽  
Tumor Infiltrating Lymphocytes ◽  
Oropharyngeal Squamous Cell Carcinoma ◽  
Hpv Status ◽  
Infiltrating Lymphocytes

Tumor growth and survival requires a particularly effective immunosuppressant tumor microenvironment (TME) to escape destruction by the immune system. While immunosuppressive checkpoint markers like programmed cell death 1 ligand (PD-L1) are already being targeted in clinical practice, lymphocyte-activation-protein 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and V-domain Ig suppressor of T cell activation (VISTA) inhibitors are currently under investigation in clinical trials. Reliable findings on the expression status of those immune checkpoint inhibitors on tumor-infiltrating lymphocytes (TILs) in the TME of oropharyngeal squamous cell carcinoma (OPSCC) are lacking. This work aims to describe the expression of LAG-3, TIM-3, and VISTA expression in the TME of OPSCC. We created a tissue microarray of paraffin-embedded tumor tissue of 241 OPSCC. Expression of the immune checkpoint protein LAG-3, TIM-3, and VISTA in OPSCC was evaluated using immunohistochemistry and results were correlated with CD8+ T-cell inflammation and human papillomavirus (HPV)-status. 73 OPSCC stained positive for LAG-3 (31%; HPV+:44%; HPV-:26%, p = 0.006), 122 OPSCC stained positive for TIM-3 (51%; HPV+:70%; HPV-:44%, p < 0.001) and 168 OPSCC (70%; HPV+:75%; HPV-:68%, p = 0.313) for VISTA. CD8+ T-cells were significantly associated with LAG-3, TIM-3 and VISTA expression (p < 0.001, p < 0.001, p = 0.007). Immune checkpoint therapy targeting LAG-3, TIM-3, and/or VISTA could be a promising treatment strategy especially in HPV-related OPSCC. Future clinical trials investigating the efficacy of a checkpoint blockade in consideration of LAG-3, TIM-3, and VISTA expression are required.

scholarly journals Evaluation of PD-L1 Expression and Associated Tumor-Infiltrating Lymphocytes in Laryngeal Squamous Cell Carcinoma

2015 ◽  
Vol 22 (3) ◽  
pp. 704-713 ◽  
Author(s):  
Maria Vassilakopoulou ◽  
Margaritis Avgeris ◽  
Vamsidhar Velcheti ◽  
Vassiliki Kotoula ◽  
Theodore Rampias ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Laryngeal Squamous Cell Carcinoma ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes

scholarly journals Tumor-Infiltrating Lymphocytes in the Tumor Microenvironment of Laryngeal Squamous Cell Carcinoma: Systematic Review and Meta-Analysis

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 486
Author(s):  
Juan P. Rodrigo ◽  
Mario Sánchez-Canteli ◽  
Fernando López ◽  
Gregory T. Wolf ◽  
Juan C. Hernández-Prera ◽  
...  
Keyword(s):  
Systematic Review ◽  
Squamous Cell Carcinoma ◽  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Prognostic Value ◽  
Laryngeal Squamous Cell Carcinoma ◽  
Meta Analysis ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes

The presence of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment has been demonstrated to be of prognostic value in various cancers. In this systematic review and meta-analysis, we investigated the prognostic value of TIL in laryngeal squamous cell carcinoma (LSCC). We performed a systematic search in PubMed for publications that investigated the prognostic value of TIL in LSCC. A meta-analysis was performed including all studies assessing the association between TIL counts in hematoxylin-eosin (HE)-stained sections, for CD8+ and/or CD3+/CD4+ TIL and overall survival (OS) or disease-free survival (DFS). The pooled meta-analysis showed a favorable prognostic role for stromal TIL in HE sections for OS (HR 0.57, 95% CI 0.36–0.91, p = 0.02), and for DFS (HR 0.56, 95% CI 0.34–0.94, p = 0.03). High CD8+ TIL were associated with a prolonged OS (HR 0.62, 95% CI 0.4–0.97, p = 0.04) and DFS (HR 0.73, 95% CI 0.34–0.94, p = 0.002). High CD3+/CD4+ TIL demonstrated improved OS (HR 0.32, 95% CI 0.16–0.9, p = 0.03) and DFS (HR 0.23, 95% CI 0.10–0.53, p = 0.0005). This meta-analysis confirmed the favorable prognostic significance of TIL in LSCC. High stromal TIL evaluated in HE sections and intra-tumoral and stromal CD3+, CD4+ and/or CD8+ TIL might predict a better clinical outcome.

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